LAPAROSCOPIC VERSES OPEN SURGICAL MANGEMENT OF THE TUBAL PREGANCY AND ITS EFFECTS ON FUTURE PREGNANCY.

Dr. Amardeep Bhimrao Tembhare
MD (Obs & Gyn), DMAS
Gynecological Specialist and Laparoscopic Surgeon
Member of World Association of Laparoscopic Surgery (WALS)
Member of Federation of Obstetrics and Gynaecological Societies of India (FOGSI) (Regd.)

Address for Correspondence
1. Aadarsha Nagar, Near Hutatma Smarak
Sevagram, Wardha, Maharashtra INDIA
Email: sb_amardeep9859@yahoo.co.in

ABSTRACT:-

Ectopic pregnancy is the most common cause of maternal death in early pregnancy and its incidence is rising. Most of the ectopic pregnancies occur in the young age group and subsequent fertility is an important issue. There is no consensus in the literature regarding laparoscopic conservative versus radical treatment of tubal pregnancy in terms of future reproductive performance. There are no randomized controlled trials of sufficient power, and meta-analysis of studies has shown different results with different investigators. But in certain studies laparoscopic surgery has advantages over open surgery and results in higher rates of subsequent intrauterine pregnancies and a lower rate of ectopic pregnancy.

BACKGROUND:-

In the treatment of tubal ectopic pregnancy (EP), laparoscopic surgery remains the cornerstone of treatment (Cochrane Database 2007). In the absence of randomized data, the question as to whether surgical treatment should be performed either conservatively (salpingostomy) or radically (salpingectomy) in women with desire for future pregnancy is subject to ongoing debate (Mol et al 2008).
Since the first study demonstrated the potential effectiveness of salpingostomy, this treatment has been compared with salpingectomy in numerous non-randomized studies (Stromme et al 1962, Mol et al 2008). Pooled data showed no beneficial effect of salpingostomy on intra uterine pregnancy (IUP) whereas there is an increased risk of repeat EP (Clausen 1996, Yao et al 1997, Mol et al 2008). Based on these findings, the Royal College of Obstetricians and Gynaecologists guideline advises salpingectomy as the preferred standard surgical approach for tubal EP (RCOG 2004). However, there are good reasons to question this advice. Interpretation of the pooled data is troublesome since many of the original studies failed to report essential details, e.g. time to pregnancy, presence of the desire for future pregnancy and whether subsequent pregnancies occurred either spontaneously or after fertility treatment, such as in vitro fertilization (IVF). Only a few non-randomized studies have taken these matters into account and came to different conclusions (Silva et al 1993, Job-Spira et al 1996, Mol et al 1998, Bouyer et al 2000, Bangsgaard et al 2003, Tahseen et al 2003, Mol et al 2008). The IUP rates were higher and the time to an IUP was shorter after salpingostomy compared to salpingectomy. Especially in women with a history of bilateral tubal pathology, salpingostomy offered better IUP rates than salpingectomy, albeit at the cost of an increased risk for repeat EP (Silva et al 1993, Job-Spira et al 1996, Mol et al 1998, Bangsgaard et al 2003, Mol et al 2008). In women without a history of tubal pathology this benefit was less clear and also in these women there was an increased risk for repeat EP (Mol et al 1998, Mol et al 2008). In view of these data, it has been felt that the most effective type of surgery for women with a tubal EP in the presence of contra lateral tubal pathology with desire for future pregnancy is salpingostomy. In women without contra lateral tubal pathology, the most optimal surgical treatment is currently unknown.

INTRODUCTION:-

Lawson Tait the father of gynecologic surgery reported the first successful operation for ectopic pregnancy in 1883. His main difficulty lay in establishing the diagnosis (Tait RL 1884).
Until a little more than decade ago, little change had occurred in the diagnosis and management of ectopic pregnancy. The clinical use of sensitive pregnancy testing, transvaginal ultrasonography and diagnostic laparoscopy has had a major impact on the preoperative diagnosis of this condition. The rate of ectopic rupture has declined, and the option of conservative surgical management of an unruptured fallopian tube is now a viable alternative.

INCIDENCE AND RISK FACTORS:-

Ectopic pregnancy is the most common cause of maternal death in early pregnancy (RCOG 1997-1999) and its incidence is rising. Most of the ectopic pregnancies occur in the young age group and subsequent fertility is an important issue. Ectopic pregnancy is a pregnancy in which the fertilized ovum implants outside the uterine cavity. Its incidence has increased from 0.5 per 100 pregnancies thirty years ago, to the present day of 2 per 100 pregnancies (Hankins et al 1995, Lehner et al 2000). The Centre for Disease Control (CDC) reports that the incidence of ectopic pregnancies is 1 in 70 pregnancies (Hill et al 1993).

Further, an increased incidence of sexually transmitted infections, earlier diagnosis of pelvic inflammatory disease resulting in tubal damage but not complete blockage, complications of infections, including therapeutic abortions, the wide clinical use of reconstructive tubal surgery, exposure to diethylstilbestrol, and the conservative surgical treatment of ectopic pregnancy and the rise in the number of ectopic pregnancies resulting from assisted reproductive technologies (ART) may account for the overall increase (Westrom et al 1991,Chungt et al 1992, Majumdar et al 1983, Wolf et al 1980 DeCherney et al 2008). The incidence of tubal pregnancy after oocyte retrieval/embryo transfer may be as high as 4.5%, although this may be due to already existing tubal pathology in these patients and not solely to ART intervention. The incidence of heterotopic pregnancy is now believed to be about 1:4,000 in the general population and 1-3% in in-vitro fertilization (IVF) pregnancies, much higher than the originally described prevalence of 1:30,000 in the late 1940s (Symonds et al 1998, Seeber et al 2006).

Critical review of the relative contributions of these factors is pertinent. It is widely accepted that when pregnancy occurs in a woman using an IUD, there is an increased likelihood of an ectopic pregnancy. Indeed, the ratio of ectopic pregnancy to intrauterine pregnancy has been reported to have increased sevenfold (Lehfold et al 1970, Vesset et al 1974, Mol et al 2008).

MANAGEMENT:-

For most tubal ectopic pregnancies (EP) surgery is the treatment of first choice. Whether surgical treatment should be performed conservatively (salpingostomy) or radically (salpingectomy) and also laparoscopically or by laparotomy in women wishing to preserve their reproductive capacity, is subject to debate. Salpingostomy preserves the tube, but bears the risks of both persistent trophoblast and repeat ipsilateral tubal EP. Salpingectomy, avoids these risks, but leaves only one tube for reproductive capacity (Mol et al 2008).

In first trimester, ectopic pregnancy is the most important cause of maternal mortality and
morbidity (Akbar et al 2002). Prior to 1883, no women ever underwent a deliberate and successful operation for a ruptured ectopic pregnancy when Trait did it for the first time. Surgical treatment may either be an open laparotomy or laparoscopic depending on the surgeon’s skill, equipment availability and condition of the patient (Braun et al 2005). Over the past few decades, the management of ectopic pregnancy has been revolutionized. This has resulted in emergence of several non-surgical options to what had once been thought to be a solely surgically treatable condition. An earlier diagnosis can be made with transvaginal (TVS) ultrasound and quantitative ß-hCG. This increases the chances of success of medical treatment and minimizes the morbidity, mortality and financial burden created by this health problem (Sawter et al 2001, Braun et al 2005). Non-surgical management like treatment with Methotrexate has an established role in the treatment of ectopic pregnancy (Grudzinskas et al 1999, RCOG 2004) but little data are available on international scale.

AIMS AND OBJECTIVES

The aim of the review is to summarize the role of minimal access surgery as in the management of tubal pregnancy and its management options and further their effect on future pregnancy.

KEY WORD

Ectopic pregnancy, operative laparoscopy, laparoscopic, laparotomy salpingectomy, surgical treatment, minimal access surgery, future pregnancy.

MATERIAL AND METHOD

A literature search was performed using the search engine Pub med, Yahoo, Wikipedia, Google, highwire press and springerlink. Selected papers were taken for the further references. All articles, RCT, (randomized controlled trial) following predominantly laparoscopic and open surgical protocol were included for review. The articles also reviewed on the elements like study of follow up on subsequent fertility, explored in terms of intrauterine pregnancy, recurrence of ectopic pregnancy and sterility, or in cumulative intrauterine pregnancy rates, was comparable or superior to that of the principle series treated by laparotomy, whether radical or conservative and using or not using microsurgical techniques. Also comparision between the theurapeutic techniques (laparotomy or laparoscopy) has been made in view of present and future pregnancy outcome.

The techniques evaluated during the review were
1. Laparoscopic
Linear Salpingiotomy (tubal aspiration)
Salpingectomy
Fimbrial expression
2. Laparotomy

LAPAROTOMY VERSUS LAPAROSCOPY

A number of early studies documented the appropriateness of laparoscopic treatment of ectopic pregnancies (Shapiro et al 1973, Bruhat et al 1980, DeCherney et al 1981, 2008). Rates of conception of an intrauterine pregnancy after the procedure were as high as 70% in these cases. Pouly and associates (Pauly et al 1986) reported on 321 women with ectopic pregnancies who underwent conservative laparoscopic treatment. Of the women who did not have a history of infertility or a previous ectopic pregnancy, 86% had a subsequent intrauterine pregnancy.
The advantages of laparoscopic removal of an ectopic pregnancy are a shortened operating time, convalescence, and hospital stay. It is imperative, however, that proper case selection be exercised (Brumsted et al 1988, DeCherney et al 2008). If laparoscopic therapy is to be warranted, the first criterion is the expertise of the operator in performance of a laparoscopic surgical procedure. Patients must be stable without evidence of a significant hempperitoneum.
One of the complications of conservative surgery via laparoscopy, persistent ectopic pregnancy, appears to be higher with laparoscopy (5–20% vs. 2–11%). This is thought to be associated with the learning curve seen with laparoscopy. Optimally, the ectopic pregnancy should be confined to the ampullary portion of the tube and should at least 2 cm in size (Lipscomb et al 2005, DeCherney et al 2008).

DISCUSSION

The incidence of ectopic pregnancy has remained static in recent years i.e. 11.1/1000
pregnancies (RCOG 2004. Bangesh et al 2004, Wasim et al 2004, Lozean et al 2005. In this study the rate was found to be 10/1000 deliveries, which is comparable. Ectopic pregnancy affects young women. The mean age was found to be 28 years and majority of them were
multigravida. The commonest presenting symptom was abdominal pain (100%). These results are comparable with other studies (Bangesh et al 2004, Wasim et al 2004, Ben et al 2006).

Historically, the treatment of ectopic pregnancy was emergency laparotomy and salpingectomy. Nowadays laparoscopic treatment is being considered the gold standard in hemodynamically stable patients particularly where expertise is available. To minimize the morbidity, mortality and financial burden created by this rapidly growing health problem, non surgical alternatives are increasingly being investigated (Korhoren et al 1996, Lozean et al 2005).
Minimal access surgery as an operative choice for management of life threatening condition like ectopic pregnancy lead to increased quality of life in term of shorter hospital stay, speedy postoperative recovery, reduce need of post operative analgesia, cosmetically good scar and less psychological trauma to the patients.
Karsten et al (1990) also favored the laparoscopy over the laparotomy; He concluded that Endoscopic management of ectopic pregnancy is recommended due to low post-operative morbidity rates and short time of hospitalization and also positive effect on future pregnancy.

Pauli et al 1991 in their study also commented that, in the absence of the few rare contraindications, the most satisfactory surgical treatment of extrauterine pregnancy at present was laparoscopic. The authors found in their series of 223 patients desiring subsequent pregnancy that factors significantly affecting the fertility prognosis included the presence of adhesions on the tube, the condition of the contralateral tube, and a history of salpingitis. Neither age, parity, nor the characteristics of the extrauterine pregnancy significantly affected the possibility of pregnancy in future.

In the era of Laparoscopic carbon dioxide laser surgery Langebrekke et al (1993) suggested in his study of 150 women with tubal pregnancy consecutively treated over a two year period by laparoscopic techniques. Sixty-six percent (38/58) of those women who desired pregnancy after conservative laparoscopic treatment achieved an intrauterine pregnancy. The corresponding rate for women who desired pregnancy after salpingectomy was 45% (18/40). The recurrent ectopic pregnancy rates in the two groups were 7% (4/58) and 10% (4/40), respectively. This study confirms that tubal pregnancy can be appropriately managed by laparoscopic laser surgery with the advantages of minimal invasive techniques and also the laparoscopic management helps for better fertility outcome in the future.

Oelsner et al (1994) studied that the reproductive performance following salpingectomy did not differ significantly, whether by laparotomy or laparoscopy: the intra-uterine pregnancy rate was 78 and 64%, respectively and the repeat ectopic pregnancy rate was 12 and 6%, respectively. Salpingectomy via laparoscopy can be performed safely with a low incidence of complications, with subsequent reproductive performance comparable to laparotomy.

Akrong et al (1996) in his two year retrospective study reviewed that the outcome of laparoscopic management versus laparotomy for the management of ectopic pregnancy. He found that there was no significant difference between the operating times and complications but the laparoscopy group had significantly fewer doses of opiate analgesia (P<0.05), shorter length of stay (P<0.05), and significantly higher post-ectopic intrauterine pregnancy rates (P<0.05) compared with the laparotomy group. Laparoscopic management of ectopic pregnancy is a viable alternative to conventional laparotomy in district general hospitals also.

Lundoff (1997) conducted a randomized, prospective clinical trial to compare the efficacy of laparoscopic treatment versus conventional conservative abdominal surgery for tubal pregnancy and concluded that patients treated by laparoscopy had a shorter hospital stay and a shorter convalescence than patients from the laparotomy group.

Lo et al (1999) performed a prospective nonrandomized multicentre study to compare laparoscopic surgery and laparotomy in the immediate surgical outcome of tubal ectopic pregnancy (TEP), at 9 teaching hospitals in Hong Kong. After exclusion of patients with shock, laparoscopic surgery offered a significantly shorter postoperative hospital stay (mean 2.7 days versus 5.3 days), a slightly lower perioperative complication rate (8.1% versus 13.9%) and more conservative surgery (90.1% of all salpingotomies) than laparotomy. A longer operating time was needed for laparoscopic surgery (1.2 hours versus 1.01 hours) which was not statistically significant. .

Saleh et al (2003) in his study suggested that there were significant reductions of total blood loss, number of blood transfusion units, and duration of hospital stay, in the laparoscopic group compared to the laparotomy group. The rates of subsequent intrauterine pregnancy were 74% (17/23) in the laparoscopy group and 61%, (19/31) in the laparotomy group and the rates of subsequent ectopic pregnancy were 4% (1/23) in the laparoscopy group and 10% (3/31) in the laparotomy group concluding that laparoscopic treatment of ectopic pregnancy in hemodynamically stable patients offers major economic benefits superior to laparotomy in terms of less need for blood transfusion, shorter duration of hospital stay and convalescence and future pregnancy outcome.

Tahseen et al (2003) concluded that laparoscopic surgery has advantages over open surgery and results in higher rates of subsequent intrauterine pregnancies and a lower rate of ectopic pregnancy. Authors also concluded that the higher intrauterine pregnancy (IUP) rates after salpingotomy (2-23% higher IUP rates) than after salpingectomy.

Becker et al (2009) raised a concern as most ectopic pregnancy cases now diagnosed and treated early future reproductive outcome needs to be evaluated critically. Authors evaluate long-term reproductive outcome after salpingotomy versus salpingectomy in patients with and without additional fertility-reducing factors and found that the laparoscopic salpingotomy is of particular benefit for patients with additional fertility-reducing factors desirous of future pregnancy. Reproductive outcome is excellent in patients without such risk factor, irrespective of the surgical approach.
Zhang et al (2010) favored the treatment of ectopic pregnancy with laparoscopic approach. In their study of 226 cases from January 2003 to December 2008 authors concluded that in order to preserve fertility, laparoscopic conservative surgery was a safe and feasible approach in treatment of tubal pregnancy. A word of caution added and it is that the preoperative serum hCG levels, size of tube gestational sac were significant factors influencing successful laparoscopic surgery.

Cochrane Database review suggest the different conclusions over the different issues like intraoperative bleeding, hospital stay, need for intraoperative blood transfusion, hospital stay, cost, recurrence of the ectopic pregnancy and future pregnancy. Cochrane database (2007) reviewed the various treatment options and commented that the laparoscopic conservative surgery is significantly less successful than the open surgical approach in the elimination of tubal pregnancy due to a higher persistent trophoblast rate of laparoscopic surgery. Long term follow-up shows similar tubal patency rates, whereas the number of subsequent intrauterine pregnancies is comparable, and the number of repeat ectopic pregnancies lowers, although these differences are not statistically significant. The laparoscopic approach is less costly as a result of significantly less blood loss and analgesic requirement, and a shorter duration of operation time, hospital stay, and convalescence time.

Supporting the Cochrane Database 2007, Desroque et al (2010) reviewed twenty-four papers of randomized control trial (RCT) or observational studies and concluded that there is no difference between laparotomy and laparoscopy for fertility was found.

CONCLUSION

Critical overview of literature of all possible approach demonstrate that the minimally access surgery is not only save and effective, but also economical then open laparotomy in the treatment of ectopic pregnancy and should consider as the gold standard in treating in ectopic pregnancy. Not only in terms of short term advantages of surgery, but it also had positive effects on the future pregnancy. Though certain studies and Cochrane database and other recent studies shows no significant difference between the surgical and future pregnancy outcome but it also mentions the need for further properly organized, randomized controlled clinical trials. But from the past literature and the ongoing research, a hopeful picture can be drawn about the laparoscopic management of ectopic pregnancy.

REFERENCES

1. Hankins GD, Clark SL, Cunningham FG, Gilstrap LC. Ectopic pregnancy. In: Dilmond E; Gilstrap. Operative obstetrics. New York: Appleton & Lange; 1995:437-56.
2. Lehner R, Kucera E, Jirecek S, Egarter C, Husslein P. Ectopic pregnancy. Arch Gynecol Obstet 2000; 263: 87-92.
3. Hill GA, Herbert CM. Ectopic pregnancy. In: Herbert CM, Textbook of gynaecology. Philadelphia: WB Saunders 1993; 242-60.
4. Symonds I M. Modern management in ectopic pregnancy, Current obstetricians & gynecology 1998; 8:27-31.
5. Desroque D, Capmas P, Legendre G, Bouyer J, Fernandez H. Fertility after ectopic pregnancyJ Gynecol Obstet Biol Reprod (Paris):2010 May 15.
6. Zhang J, Hao WM, Wei W, Zhang DW, Li YN. Outcome and relevant factors of tubal pregnancy treated with laparoscopic conservative surgery Zhonghua Fu Chan Ke Za Zhi: 2010 Feb; 45(2):84-8.
7. Becker S, Solomayer E, Hornung R, Kurek R, Banys M, Aydeniz B, Franz H, Wallwiener D, Fehm T. Optimal treatment for patients with ectopic pregnancies and a history of fertility-reducing factors.Arch Gynecol Obstet 2009 Nov 10. [Epub ahead of print] [Pubmed]
8. Akbar N, Shami N, Anwar S, Asif S. Evaluation of predisposing factors of tubal pregnancy in multigravidas versus primigravidas. J Surg PIMS 2002; 25: 20-3.
9. Braun RD. Surgical management of ectopic pregnancy. Online 2005. e medicine. [Cited 2005 Oct 27].Available from: URL://www.emedicine.com/med/topic 3316.htm-94k.
10. Sowter MC, Farquhar CM, Petrie KJ, Gudex G. A randomized trial of comparing single dose systemic methotrexate and laparoscopic surgery for the treatment of unruptured tubal pregnancy. Br J Obstet Gynecol 2001; 108:192-203.
11. Grudzinskas JG. Miscarriage, ectopic pregnancy and trophoblastic disease. In: Edmonds DK. Dewhurst’s textbook of obstetrics and gynaecology for postgraduates. 6th ed. Oxford: Blackwell Science 1999; .61-75.
12. The management of tubal pregnancy. Royal college of obstetricians and gynecologists guidelines 2004; 21:1-10.
13. Seeber BE, Barnhart KT. Suspecting ectopic pregnancy. Obstet Gynecol 2006; 107:399-413.
14. Westrom L, Bengtsson LPH, Mardh PA: Incidence trends, and risks of ectopic pregnancy in a population of women. Br Med J (Clin Res) 282: 15, 1981.
15. Chung CS, Smith RG, Steinhoff PG et al: Induced abortion and ectopic pregnancy in subsequent pregnancies. Am J Epidemiol 1982; 115: 879.
16. Majumdar BH, Henderson PH, Semple L: Salpingitis isthmica nodosa: A high-risk factor for tubal pregnancy. Obstet Gynecol 1983; 62: 73.
17. Wolf GC, Thompson NJ: Female sterilization and subsequent ectopic pregnancy. Obstet Gynecol: 1980; 55: 17.
18. DeCherney, A, Agel, W, et al, Glob. libr. women's med. (ISSN: 1756-2228) 2008; DOI 10.3843/GLOWM.10047, August 2008.
19. Mol F. Strandell A. Jurkovic D. Talcinkaya T. Verhoeve HR. Koks AM. Linden P. Graziosi G. Thurkow AL. Hoek A. Hangstrom L. Klinte I. Nilsson K. Mello N. Ankum W. Veen F. Mol B. Hajenius PJ. ESEP study: Salpingostomy versus salpingectomy for tubal ectopic pregnancy; The impact on future fertility: A randomized controlled trial. BMC Women's Health 2008, 8:11doi:10.1186/1472-6874-8-11.
20. Lehfeld H, Tietze C, Gorstein F: Ovarian pregnancy and the intrauterine device. Am J Obstet Gynecol: 1970; 108: 1005.
21. Vessey MP, Johnson B, Doll R et al: Outcome of pregnancy in women using an intrauterine device. Lancet 1: 495, 1974
22. Hajenius PJ, Mol F, Mol BW, Bossuyt PM, Ankum WM, Veen : Interventions for tubal ectopic pregnancy. Cochrane Database Syst Rev 2007(1):CD000324. [Pubmed]
23. Stromme WB, McKelvey JL, Adkins CD: Conservative surgery for ectopic pregnancy. Obstet Gynecol 1962 , 19:294-301. [Pubmed]
24. Clausen I: Conservative versus radical surgery for tubal pregnancy. Acta Obstet Gynecol Scand 1996 , 75:8-12. [Pubmed]
25. Yao M, Tulandi T: Current status of surgical and nonsurgical management of ectopic pregnancy. Fertil Steril 1997, 67:421-33. [Pubmed]
26. Royal College of Obstetricians and Gynaecologists: The management of ectopic pregnancy. In Guideline No 21. RCOG Press; 2004.
27. Silva P, Schaper A, Rooney B: Reproductive outcome after 143 laparoscopic procedures for ectopic pregnancy. Fertil Steril 1993, 81:710-5.
28. Job-Spira N, Bouyer J, Pouly JL, Germain E, Coste J, Aublet-Cuvelier B, Fernandez H: Fertility after ectopic pregnancy: first results of a population-based cohort study in France.Hum Reprod 1996, 11:99-104.
29. Mol BWJ, Matthijse HC, Tinga DJ, Huynh T, Hajenius PJ, Ankum WM, Bossuyt PMM, Veen van der F: Fertility after conservative and radical surgery for tubal pregnancy. Hum Reprod 1998, 13:1804-9.
30. Bouyer J, Job-Spira N, Pouly JL, Coste J, Germain E, Fernandez H: Fertility following radical, conservative-surgical or medical treatment for tubal pregnancy: a population-based study.BJOG 2000 , 107(6):714-21
31. Bangsgaard N, Lund CO, Otessen B, Nilas L: Improved fertility following conservative surgical treatment of ectopic pregnancy.Br J Obstet Gynecol 2003, 110:765-70.
32. Tahseen S, Wijldes M: A comparative case controlled study of laparoscopic versus laparotomic management for ectopic pregnancy: an evaluation of reproductive performance after radical versus conservative treatment of tubal ectopic pregnancy. Am J Obstet Gynaecol 2003, 23:189-90.
33. Tait RL: Five cases of extrauterine pregnancy operated upon at the time of pregnancy. Br Med J 1: 1250, 1884.
34. The management of tubal pregnancy. Royal college of obstetricians and gynecologists guidelines 2004; 21:1-10.
35. Lozean AM, Potter B. Diagnosis and management of ectopic pregnancy. Am Fam Physician 2005; 72:1707-14.
36. Bangash N, Ahmed H. A study of 65 cases of ectopic pregnancy during one year period in military hospital. Pak Armed Forces Med J 2004; 54:205-8.
37. Wasim T. Proportionate morbidity and risk factors of ectopic pregnancy. Ann King Edward Med Coll 2004; 10:298-300.
38. Ben Hmid R, Mahjoub S, Mourali M, El Houssaini S, Zeqhal D, Zouari F, et al. Management of ectopic pregnancy. Tunis Med 2006; 84:238-41.
39. Korhoren J, Stenman UH, Ylostalo P. Methotrexate with expectant management of ectopic pregnancy. Obstet Gynecol 1996; 88:775-8.
40. Bruhat MA, Manhes H, Mage G et al: Treatment of ectopic pregnancy by means of laparoscopy. Fertil Steril 33: 411, 1980
41. Shapiro HI, Adler DLH: Excision of an ectopic pregnancy through the laparoscope. Am J Obstet Gynecol: 1973; 117: 290,
42. DeCherney AH, Romero R, Naftolin F: Surgical management of unruptured ectopic pregnancy. Fertil Steril: 1981; 35: 21,
43. Pouly JL, Mahnes H, Mage G et al: Conservative laparoscopic treatment of 321 ectopic pregnancies. Fertil Steril: 1986; 46: 1093,
44. Brumsted J, Kessler C, Cison C et al: A comparison of laparoscopy and laparotomy for the treatment of ectopic pregnancy. Obstet Gynecol; 1988; 71: 889,
45. Lipscomb GH, Givens VM, Meyer NL et al: Comparison of multidose and single-dose methotrexate protocols for the treatment of ectopic pregnancy. Am J Obstet Gynecol 2005; 192(6):1844-7.
46. Karsten U, Seifert B Introduction and results in the endoscopic treatment of extrauterine pregnancy 1990; 112(8):467-73.
47. Tahseen S, Wyldes M. A comparative case-controlled study of laparoscopic vs. laparotomy management of ectopic pregnancy: an evaluation of reproductive performance after radical vs. conservative treatment of tubal ectopic pregnancy J Obstet Gynaecol 2003 Mar; 23(2):189-90.
48. Oelsner G, Goldenberg M, Admon D, Pansky M, Tur-Kaspa I, Rabinovitch O, Carp HJ, Mashiach S. Salpingectomy by operative laparoscopy and subsequent reproductive performance. Human Reprod. 1994 Jan; 9(1):83-6